PROJECT ABSTRACT Lung cancer is the most common and highest mortality type of cancer and is frequently the result of activating mutations to the epidermal growth factor receptor (EGFR). Due to the emergence of resistance mutations in patients treated with EGFR inhibitors, allosteric inhibitors targeting EGFR mutants have shown promise as the next generation of therapeutics. With their distinct binding sites, canonical, ATP-competitive inhibitors can bind simultaneously and cooperatively with allosteric inhibitors to synergistically kill cancer cells in vivo. Combination of EGFR inhibitors with different mechanisms of action represents a new paradigm for targeting tumors that are refractory to current monotherapies through the exploitation of cooperative binding principles. The long-term goal of this project is to understand the mechanism of action of cooperative kinase inhibitor binding to oncogenic and drug resistant variants of EGFR to aid in the development of novel combination therapies for EGFR-driven lung cancers. Structural and pharmacological methods will be used to define cooperative binding mechanisms and synergy of different combinations of ATP-competitive and allosteric inhibitors in the context of clinically-relevant EGFR variants to understand the effects of these mutations on co-binding. Insights garnered from these studies will be used to rationally design and synthesize complimentary pairs of inhibitors with enhanced cooperativity. The resulting inhibitor combinations may be able to overcome common resistance mutations or display enhanced selectivity for oncogenic variants of EGFR over wild-type. The proposed project will take place at the Dana-Farber Cancer Institute (DFCI), a leading research center for cancer research, and will benefit greatly from its strong translational therapeutics program. The proposed project takes into account the trainee?s strengths in protein biochemistry and structural biology while providing training in medicinal chemistry and cancer biology. Through DFCI?s affiliation with Harvard Medical School, the trainee will take courses in cancer cell biology and synthetic chemistry, present at departmental seminars and conferences, and mentor students. The sponsors of this project are experts in the fields of EGFR pharmacology and kinase inhibitor chemistry and will allow the trainee to assist in writing relevant grant proposals to provide training in technical writing and budgeting. The trainee will be the primary contact with regard to project collaborations and will be in charge of initiating and coordinating manuscripts describing the results of this project.